1. Field of the Invention
The invention relates to a method for inducing a homologous protection against the 4 dengue serotypes in a patient, comprising the sequential administration, to said patient, (i) of a dose of a vaccinal dengue virus of a first serotype and of a dose of a vaccinal dengue virus of a second serotype, and (ii) of a dose of a vaccinal dengue virus of a third serotype and of a dose of a vaccinal dengue virus of a fourth serotype, in which the vaccinal dengue viruses (ii) are administered at least 30 days and at most 1 year after administration of the vaccinal dengue viruses (i).
2. Summary of the Related Art
Dengue diseases are caused by four viruses of the flavivirus genus, of the serological type, which are similar but distinct from an antigenic point of view (Gübler et al., 1988 In: Epidemiology of arthropod-borne viral disease. Monath TPM, editor, Boca Raton (Fla.): CRC Press: 223-60; Kautner et al., 1997, J. of Pediatrics, 131:516-524; Rigau-Pérez et al., 1998, Lancet; 352: 971-977; Vaughn et al., 1997, J Infect Dis; 176: 322-30). Infection with a dengue serotype can produce a clinical disease spectrum ranging from a nonspecific viral syndrome to a severe hemorrhagic disease which is fatal. The incubation period of dengue fever after a mosquito bite is approximately 4 days (ranging from 3 to 14 days). Dengue fever is characterized by a biphasic fever, headaches, pain in various parts of the body, prostration, eruptions, lymphadenopathy and leukopenia (Kautner et al., 1997, J. of Pediatrics, 131:516-524; Rigau-Pérez et al., 1998, Lancet; 352: 971-977). The viremia period is the same as for febrile diseases (Vaughn et al., 1997, J. Infect. Dis.; 176: 322-30). Recovery from dengue fever occurs after 7 to 10 days, but there is usually a prolonged asthenia. Decreases in leukocyte and platelet count are common.
Hemorrhagic dengue is a severe febrile disease characterized by anomalies in homeostasis and an increase in vascular permeability which can result in hypovolemia and in hypotension (dengue with shock syndrome) often complicated by severe internal hemorrhaging. The mortality rate of hemorrhagic dengue can be up to 10% without treatment, but is 1% in most centers with experience in treatment (WHO technical Guide, 1986. Dengue haemorrhagic fever: diagnosis, treatment and control, p1 -2. World Health Organization, Geneva, Switzerland).
The routine laboratory diagnosis of dengue is based on isolation of the virus and/or detection of antibodies specific for the dengue virus.
Dengue is the second most common tropical infectious disease after malaria, more than half the world's population (2.5 billion) living in regions where there is a risk of epidemic transmission. Each year, cases of dengue are estimated at 50-100 million, cases of patients hospitalized for hemorrhagic dengue at 500 000, and the number of deaths at 25 000. Dengue is endemic in Asia, in the Pacific region, in Africa, in Latin America and in the Caribbean. More than 100 tropical countries are endemic for dengue virus infections and hemorrhagic dengue has been documented in 60 of these countries (Gubler, 2002, TRENDS in Microbiology. 10:100-103; Monath, 1994, Proc. Natl. Acad. Sci.; 91: 2395-2400). A certain number of well-described factors appear to be involved in dengue: population growth; unplanned and uncontrolled urbanization, in particular in combination with poverty; an increase in air travel; the lack of effective control of mosquitoes and the deterioration of hygiene infrastructures and of public health (Gubler, 2002, TRENDS in Microbiology. 10: 100-103). Individuals who travel and expatriates are increasingly warned about dengue (Shirtcliffe et al., 1998, J. Roy. Coll. Phys. Lond.; 32: 235-237). Dengue has constituted one of the main causes of febrile diseases in American troops during deployments in tropical zones endemic for dengue (DeFraites et al., 1994, MMWR 1994; 43: 845-848).
The viruses are maintained in a cycle which involves humans and Aedes aegypti, a domestic mosquito which bites during the day, and which prefers to feed off humans. The infection in humans is initiated by injection of the virus while an infected Aedes aegypti mosquito feeds on the blood. The virus in the saliva is deposited mainly in the extravascular tissues. The first category of cells infected after inoculation are dendritic cells, which then migrate to the lymph nodes (Wu et al., 2000, Nature Med.; 7:816-820). After an initial replication in the skin and in the lymph nodes, the virus appears in the blood during the acute febrile phase, generally for 3 to 5 days.
Monocytes and macrophages are, with dendritic cells, among the first targets of the dengue virus. Protection against a homotypic reinfection is complete and probably lasts for a lifetime, but crossprotection between the various dengue types lasts less than a few weeks to a few months (Sabin, 1952, Am. J. Trop. Med. Hyg.; 1: 30-50). Consequently, an individual can experience an infection with a different serotype. A second infection with dengue is in theory a risk factor for developing a severe dengue disease. However, hemorrhagic dengue is multifactorial: these factors include the strain of the virus involved, and also the age, the immune status and the genetic predisposition of the patient. Two factors play a major role in the occurrence of hemorrhagic dengue: rapid viral replication with a high viremia (the severity of the disease being associated with the level of viremia; Vaughn et al., 2000, J. Inf. Dis.; 181: 2-9) and a substantially inflammatory response with the release of high levels of inflammatory mediators (Rothman and Ennis, 1999, Virology; 257: 1-6). There is no specific treatment against dengue. The treatment for dengue fever is symptomatic with confinement to bed, control of the fever and of the pain with antipyretics and analgesics, and adequate fluid intake. The treatment for hemorrhagic dengue requires equilibration of fluid losses, replacement of clotting factors and heparin infusion.
Preventive measures are currently based on controlling the vector and taking personal protection steps which are difficult to implement and expensive. No vaccine against dengue has been approved at this time. Given that the four dengue serotypes are in circulation in the world and since they have been reported as being involved in cases of dengue hemorrhagic fever, immunization should ideally confer protection against the four serotypes of the dengue virus.
Sequential immunization strategies have previously been implemented with the aim of inducing a heterologous protection among the various dengue serotypes.
Thus, Price (1968, Am. J. Epid., 88:392-397) has described a method of sequential immunization against dengue comprising a series of two infections with dengue serotype 1 and then with dengue serotype 2, which conferred protection in a challenge test with dengue serotype 3 or 4.
Whitehead et al. (1970, Am. J. Trop. Med. Hyg., 19:94-102) sought to determine the influence of a sequential monovalent infection with two or three of the four dengue serotypes, on the conferred heterologous immunity. Gibbons were thus initially infected with a dengue virus serotype 1, 2, 3 or 4. Following a second infection with a heterologous serotype, a variable viremia was detected which was dependent on the sequence of infection and in particular on the serotype used for the first infection. More specifically, a second viremia appeared in gibbons initially infected with serotype 2, 3 or 4 and then challenged with serotype 1, 2 or 4.
Scherer et al. (1972, Am. J. Epid., 95:67-79) described a sequential monovalent infection comprising a first infection with one of the four dengue serotypes, followed by a second infection, or even a third infection, with a homologous or heterologous serotype. The proposed schemes did not make it possible to obtain a satisfactory protection against a challenge with a heterologous serotype.
Halstead et al. (1973, Am. J. Trop. Med. Hyg., 22:365-374) evaluated, in monkeys, a method of sequential immunization against dengue comprising a series of two, three or four monovalent infections with heterologous dengue serotypes 1 to 4. The authors concluded that a protection against a subsequent infection could be obtained with the immunization sequence consisting of serotypes 1, 2 then 4, followed by a challenge with serotype 3. Bivalent immunization is neither described nor suggested. Furthermore, the authors advise against sequential immunizations due to their laborious nature and to the random nature of the results generated.
Halstead et al. (1973, Am. J. Trop. Med. Hyg., 22:375-381) also found that a bivalent immunization with two heterologous dengue serotypes did not protect, or only partially protected, against an infection with a third dengue serotype.